1,2,3,4,8,9-hexahydro-3-methylpyridol(4&#39;,3&#39;:2,3)indolo(1,7-ab)(1)benzazepine and the 3-ethyl homolog as tranquilizers

ABSTRACT

TWO KNOWN COMPOUNDS, 1,2,3,4,8,9-HEXAHYDRO-3-METHYLPYRIDO(4&#39;&#39;,3&#39;&#39;,2,3) INDOLO(1,7-AB)(1)BENZAZEPINE AND 3ETHYL-1,2,3,4,8,9-HEXAHYDROPYRIDO(4&#39;&#39;,3&#39;&#39;:2,3)INDOLO (1,7AB)(1) BENZAZEPINE, ARE EFFECTIVE BOTH AS MINOR TRANQUILIZERS (ANXIOLYTICS) AND AS MAJOR TRANQUILIZERS (ANTIPSYCHOTICS). AS MINOR TRANQUILIZERS THEY ARE EFFECTIVE AT NONATAXIC DOSES, AND ARE NOT LIKELY TO CAUSE ADDICTION WHEN ABUSED. ADDITION SALTS OF THESE COMPOUNDS WITH PHARMACEUTICALLY ACCEPTABLE ORGANIC OR INORGANIC ACIDS CAN BE USED WITH THE SAME EFFECT.

United States Patent US. Cl. 424-263 7 Claims ABSTRACT OF THE DISCLOSURE CROSS-REFERENCE TO RELATED APPLICATION This is a continuation-in-part of my copending application Ser. No. 170,991, filed Aug. 11, 1971, now abandoned.

BACKGROUND OF THE INVENTION This invention relates to the use of 1,2,3,4,8,9-hexahydro 3 methylpyrido[4',3':2,3]indolo[1,7-ab][1] benzazepine (Compound I) and of 3-ethyl-1,2,3,4,8,9- hexahydropyrido[4,3':2,3]indolo[1,7 ab][1]benzazepine (Compound 11) both as minor transquilizers (anxiolytics) and as major tranquilizers (antipsychotics).

US. 3,457,271 (to Cohen et a1.) discloses a class of organic compounds of the generic Formula 1:

where R' is a straight or branched-chain alkyl having l-7 carbon atoms. These compounds are said to have utility as antidepressants.

US. 3,373,168 (to Cohen et a1.) is directed to a process for the preparation of compounds of Formula 1, wherein the last intermediates have the following Formula 2:

where R has the same meaning as in Formula 1.

This patent discloses that the intermediate of Formula 2, in which R is methyl, and its acid addition salts, have a powerful antiserotonin and antihistamine eifect.

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South African Pat. 680,169 (to Cohen et a1.) discloses a class of compounds having the following Formula 3:

where R" is hydrogen or a straight-chain alkyl group having no more than 4 carbon atoms.

These compounds and their acid addition salts possess a marked depressant activity on the central nervous system and are useful as sedatives and tranquilizers.

None of the above references discloses or suggests that the compounds of Formula 2 in which R is methyl or ethyl themselves have tranquilizer activity, much less that they can function as either minor tranquilizers (anxiolytics) or as major tranquilizers (antipsychotics).

General, nonselective central nervous system depressants are one class of drugs well recognized in the art [L. S. Goodman and A. Gilman (Eds.), The Pharmacologic Basis of Therapeutics, 4th ed., The Macmillan Co., N.Y., 1970]. Included in this category the anesthetic 5 gases and vapors, aliphatic alcohols and the barbiturates and related sedative-hypnotic drugs. These agents share the common property of depressing all excitable tissue.

Also well recognized in the art is another class of depressant drugs known as selective central system depressants [ibid, page 40]. In contrast to the nonselective depressants, these drugs selectively affect particular central nervous system functions. Included in this category are major tranquilizers such as the phenothiazines, and minor tranquilizers exemplified by the benzodiazepins. The former, also known as antipsychotics, are used mainly in schizophrenia and other psychoses, while the latter, also known as anxiolytics, are effective in behavioral states characterized by anxiety and tension.

Most commonly used drugs, whether minor tranquilizers or major tranquilizers have undesirable side effects, including ataxia and physical dependence. There often also are undesirable pharmacological side effects which limit their usefulness, such as juandice, parkinsonism, dyskinesia, faintness, palpitation, dry mouth, and so on.

There is, therefore, a need in the art for additional psychotherapeutic agents which would have fewer side effects than those used today and which would be effective for the treatment of either neuroses or psychoses.

SUMMARY OF THE INVENTION According to the present invention, it has now been discovered that compounds having the Formula 2 above, in which R is methyl or ethyl, are useful psychotropic agents which can be used in warm-blooded animals either as minor tranquilizers or as major tranquilizers.

While in US. Pat. 3,373,168 there compounds are named ll-methyl- (and 11-ethyl-) 5, 6,10,11,12,13-hexahydro-1-benzazepino[3,2,1 hi,]pyrido [4,3- b1indole, and displayed as in above Formula 2, the preferred names,

3 based on the 1957 IUPAC is displayed and numbered as in Formula 4 below:

system depressants, such as ataxia. Of particular interest Rules, in which the structure where R is methyl or ethyl, are 1,2,3,4,8,9-hexahydro-3- methylpyrido[4,3:2,3]indolo[1,7 ab] [1]benzazepine (Compound I) and 3-ethyl-1,2,3,4,8,9-hexahydropyrido- [4',3':2,3]indolo[l,7-ab] [1]benzazepino (Compound II), respectively; rings D and E form the benzazepino portion of the molecule; rings B and C form the indolo portion; and ring A forms the pyrido portion.

In addition to the free bases themselves, their addition salts with pharmaceutically acceptable organic or inorganic acids also can be used with the same eifect.

DETAILED DESCRIPTION OF THE INVENTION The compounds of Formula 4 in which R is methyl may be made by a number of processes, for example, by the process disclosed in US. 3,457,271, wherein N-aminoiminodibenzyl hydrochloride is treated in ethanol with 1-methyl-4-piperidone; the mixture is heated, then saturated with dry hydrogen chloride; the solvent is evaporated; the residue is dissolved in water; the solution is made alkaline; and the product is extracted with chloroform. It is recovered as a solid material which can be recrystallized as a white product melting at 152153 C. The hydrochloride is reported to have a melting point of 262-264 C. The compound of Formula 4 in which R is ethyl can be prepared in the same manner. According to US. 3,457,271, its melting point is 94-95 C. and the melting point of the hydrochloride is 27 6-277 C.

Other addition salts of the above compounds with pharmaceutically acceptable organic or inorganic acids can be prepared and used instead of the free bases. Such salts are normally more water soluble. Representative acids'which can be used for this purpose include hydrochloric, hydrobromic, sulfuric, sulfamic, phosphoric, nitric, maleic, fumaric, benzoic, ascorbic, citric, pamoic, succinic, methanesulfonic, ethanedisulfonic, acetic oxalic, propionic, tartaric, salicylic, gluconic, lactic, malic, mandelic, cinnamic, citraconic, aspartic, stearic, palmitic, itaonic, glycolic, p-aminobenzoic, glutamic, and toluenesulfonic acids.

The compounds of the present invention, when administered to warm-blooded animals in efiective psychotropic doses, do not produce certain of the undesirable side ef fects commonly associated with prior art central nervous system depressants, such as ataxia. Of particular interest is the fact that these compounds, which possess both minor and major tranquilizer activities, are not likely to cause addiction when abused, because the resulting major tranquilizer efiect would be considered very undesirable by the subject. Indeed, it is well known that major tranquilizers are not subject to abuse.

The free bases of Formula 4 are substantially insoluble in water. They are best administered orally at a level of about 0.3 to 30.0 mg. per kilogram of body weight of the animal. At the lower doses, up to about 1-0 mg. per kilogram of body weight, they exhibit predominantly minor tranquilizer (anxiolytic) activity. At a higher level, their efiect is predominantly antipsychotic. The usual dossage required to produce a major tranquilizer effect is about l-30 mg. per kilogram of body weight. The relatively broad overlap between the minor tranquilizer and major tranquilizer ranges is due to difierences among various animal species.

Addition salts of Compounds I and II with pharmaceutically acceptable organic or inorganic acids are water-soluble and can be administered by subcutaneous or intramuscular injection. The dosage employed in such cases would be lower, generally within the range of 0.1 to 10 mg. per kilogram of body weight.

The pharmacological evaluation of the compounds of this invention shows that they exhibit typical major tranquilizer activity as evidenced by dose-dependent antagonism of amphetamine hyperactivity in mice, antagonism of apomorphine and amphetamine stereotype in rats, blockade of conditioned avoidance responses (C.A.R.) in mice and rats, and taming of rhesus monkeys. Most surprisingly, they also exhibit minor tranquilizer activity, manifested by antagonism of an approach-avoidance (conflict) situation in rats, and decreased fear and increased approach-behavior in the rhesus monkey. The techniques employed in the pharmacological evaluation of Compounds I and II are described below, each one preceded by the abbreviation used at the head of the column of the following table in which the quantitative results are listed:

Screen (Results given in mg./kg. p.o./mouse) Mouse screen: The minimal eflective dose (MED) is the lowest oral dose producing an obvious decrease in locomotor activity, using observational techniques. Groups of 3 mice are given decreasing oral doses at 0.5 log intervals (300, 100, 30 etc.) until no behavioral effects are evident. Decrease of locomotor activity is indicative of general central nervous system depressant activity.

A.A. (Results given in mg./kg. p.o./mouse) Mouse anti-amphetamine activity: Groups of 5 mice are given d-arnphetarnine sulfate 5 mg. /kg. so. 1 hour after oral administration of graded doses of test compounds. The mice are placed in photocell activity units immediately after amphetamine administration and locomotor activity is recorded for 60 minutes. The ED is calculated as the dose causing a 50% reduction in locomotor activity relative to the activity of the amphetamine-treated control mice. Amphetamine antagonism at non-toxic doses appears to correlate with major tranquilizer activity in man.

C.A.R. (Results given in mg./kg. p.o.lmouse, rug/kg. p.o.lrat) Mouse and rat conditioned avoidance response: Mice and rats are trained to jump out of a pit onto a ledge to avoid shock when presented with a light and sound conditioned stimulus. The animals are tested 1, 2, and 4 hours after administration of the test compound. Three to 4 dose levels and groups of 4-8 animals/dose are used. The ED is the dose producing a block of the CAR. in 50% of the animals. Blocking of the C.A.R. at non-toxic doses appears to correlate with major tranquilizer activity in man.

Taming (Results given in rug/kg. p.o./monkey) 'Rhesus monkey taming effects: Compounds are administered orally to groups of 6 rhesus monkeys. The behavior of the animals is then evaluated by observational means. Taming eficcts are determined by the ability of the observer to approach and touch the monkey. Compounds with major tranquilizer activity in man can produce a state of passive tameness in the rhesus monkey wherein it can be touched without provoking any of the threatening or aggressive behavior seen in the normal animal. The MED is the minimal oral dose at whichsome taming efiect can be observed.

Conflict (Results given in mg./kg. p.o./rat) Rat conflict (approach-avoidance) test: Food deprived rats are trained to pass from one compartment to an adjacent one to obtain food. The training consists of 3 oring agents. Some examples of the carriers which can be fi li l lie ia t s a li ii/ e igj l lilg t i 51 -2? lfr 1%; :5 1: 5 used in the preparation of the products of the invention to fo'od in their g cages on day oneand are then are gelatin capsules, sugars such as lactose and sucrose; food deprived for at least 18 hours on day two of the starches, dextrans and cellulosics, such as methyl cellulose experiment the rats are given a col'mol exposure to the and cellulose acetate phthalate; ge1atm; talc, stearlc ac d test situation followed by a second exposure after /2 to 10 Salts; vegetabie 01.15 such i cottonseed. i 1 hour in which they are shocked after crossing and sesame 011, olive oil, corn 011 and 011 of theobroma; hquid petrolatum; polyethylene glycol; glycerine; sorbitol; prolng. Groups of 6-8 rats are then dosed orally with solvent or test compound and then re-exposed to the test situation pylene glycql ethanol aga-r? water am? lsoto-mc sahne' after 1 or 2 hours In pzepanng thefiompositittms of the inventiondfor pharmaceuica uses, e conven 1ona prac ices an precauacfiiiig r r iar i h h ag dgze ggiii aiifl miigfig fiig ti ns are used. The composition intended for parenteral produce an apparent decreased fear in the test animals aqmlmstr-atlon must and can be so that they cross to obtain food despite having received phshed either i usmg Sterne. mgreqients and carrsilpg a shock earlier This eifect is dose-related (and the MED Put the production aseptlc commons or by stenhzis the minimum dose at which this effect is obtained)" mg the final composmon by one of-the usual procedures rats dosed with solvent only consistently show a high Such as autoc-le-wmg under appropnate temperature :dnd level of fear as evidenced by decreased mobilit and abpreSSure-cOndltmI-ls' CuStoI-n-ary car-e Should be exam-ed sence of feeding when placed in the test situa t ion after that no mcompatlble Fondmons ems? between 11-16 actlve receiving a shock components and the diluent preservatlve or flavormg agent or m the conditions employed in preparation of the compo- Approach (Results given in mg./kg. p.o./monkey) 9 0 p f th b t 0d d e c m os1 10I1S 0 e invenion can e in r uce Rhesusdmonl1 1ey approach efifec6tszhCompounrllis are laginto warm-blooded animals by the oral, rectal or parenministere ora y to groups 0 r esus mon eys. e teral route. This can be done b swallowin in the case behavior of the animals is then evaluated by observational of liquid or solid preparations; by supposi tories; or by means. Approach eifects are examined by determining injecting the liquid preparations intravenously, intramuswhettllier a monkey shows decreased fear as evidenced by cularly, intraperitoneally, or subcutaneously. reac ing out for food or objects or coming closer instead Typical formulations of the t e listed above which of the withdrawal behavior that is seen in the untreated may be used for the administratio ii of these compounds lizaonkeay. Compounds 1influencing this type of behavior are: ave een shown to e useful in man as minor tran- EXAMPLE A quilizer (anxiolytic) agents. The MED is the oral dose Ingredients: Mg./tablet at which the animals-show signs of decreased fear. 1,2,3,4,8,9-hexahydro 3 methylpyrido[4',3:2,

Quantitative results obtained with Compounds I and 3]indolo[l,7 ab][1]benzazepine hydrochlo- II, using the methods described above, are compared in ride 15 the following table with results obtained with chlor- Lactose, USP 183 promazine, a well-known major tranquilizer, and with Magnesium stearate, USP 2. diazepam, a well-known minor tranquilizer. Color (if desired q.s.

TABLE Screen A.A. C.A.R. C.A.R. Tamin Conflict Approach compo... ites 11 at a i list; iii3 3-5;: iifitgi g-rllififigglropyrido [4 ,3 2,3]indol0[1,7-ab][ljbenz- R= I R=. fi. dihi?ofli i1)----- 333133 i8 28 33 58133 iii?) i 52233;? I 338 12 1: i2 i i Q 34% =indicates compound has not been evaluated in this test. -=ae1ive, but also causes ataxia at this dose. I=inactive. Ia=inaetive at doses not producing ataxia.

ic =inconsistent results.

The above results show that both Compounds I and II All of the above ingredients are passed through a suitare active minor as well as ma or tranquihzers, which comable sieve, blended for 20 minutes, and compressed directp w l W1t h the known standards. 1y into tablets of 200 mg. on a suitable table press using Some addition salts of the compounds having Formula a 11 /32" punch and 4 with pharmaceutically acceptable inorganic or organic 6O acids are water-soluble and can be administered by sub- EXAMPLE B cutaneous or intramuscular injection. The dosage em- I ployed in such cases would be lower and generally would ngre lents' MgJtablet be within the range of 0.1 to 10 milligrams per kilogram 3 T hexahylrpynd[@3123] of body weight. The usual dosage for minor tranquilizer mdoloufi [nbenzazepme hydrochloride 50 activity is 0.3 to 10 mg./kg. per o.s. and for major tran- Lactose USP 215 quilizer activity 1 to 30 mg./kg. per o.s. The relatively Methylcellulose: USP 15 broad overlap between the minor tranquilizer and major Talc USP 6 tranquilizer ranges is due to differences among various Starch, USP 10 animal species. The compounds of the present invention agn sium stearate, USP 4 can be formulated into compositions comprising a compound of Formula 4 or a pharmaceutically acceptable acid addition salt thereof together with a pharmaceutically acceptable carrier. The carrier may be either a solid or 6 liquid-filled capsules, dry filled capsules, aqueous solutions, non-aqueous solutions, suppositories, syrups, suspensions and the like. The compositions can, and in many cases do contain suitable preservatives, coloring and flav- Color (if desired) q.s.

The lactose and active ingredient are Wet granulated with a solution of methylcellulose in a blender until a liquid, and the compositions can be in form of tablets, satisfactory mass is achieved. The mass is dried and classified through an appropriate sieve. The remaining ingredicuts are passed through an 80 mesh sieve and blended with the dried granulated material. The blend is then compressed into tablets on a suitable tablet press at a weight of 300 mg. using a punch and die.

EXAMPLE C Ingredients: Mg./capsu1e 1,2,3,4,8,9 hexahydro 3 methylpyrido[4,3':2,

3]indolo[l,7-ab] [llbenzazepine hydrochloride 25 Lactose, USP 100 Magnesium stearate, USP 1 Colloidal silicon dioxide, N.F. 2

The combined ingredients are blended and passed through a 40 mesh sieve, and the mixture is encapsulated into a two-piece hard gelatin No. 3 capsule on a suitable encapsulating machine at a net weight of 128 mg.

EXAMPLE D Ingredients: Grams/liter 1,2,3,4,8,9 hexahydro 3 methyl-pyrido[4',3':2,

3]indolo[1,7 ab] [1]benzazepine methanesulfonate 3 Granulated sugar 600 Sodium benzoate 1 Flavor, q.s.

Color, q.s.

Deionized water, q.s.

All of the above ingredients are dissolved in water and made up to a volume of one liter.

EXAMPLE E Ingredients: Grams/liter 3 ethyl l,2,3,4,8,9 hexahydropyrido[4,3'22,3]

indolo[1,7 ab] [1]benzazepi.ne methanesulfonate Propylparaben, USP 0.2 Methylparaben, USP 1.8

Water for injection, q.s. to 1 liter.

indolo[1,7 ab][l]benzazepine methanesulfonate 10 Propylparaben, USP 0.2 Methylparaben, USP 1.8 Sodium carboxymethylcellulose, USP (CMC) 5 Polysorbate 80, USP 1 Water for injection, q.s. to 1 liter.

The parabens, CMC and one-half of the polysorbate are dissolved in about 700 ml. of Water for injection, with agitation at 80 (solution A). A slurry is made of the active ingredient, one-half of the polysorbate 80 and about 200 ml. of water for injection (slurry B). Solution A is aseptically filtered through a millipore filter to render it sterile, while slurry B is autoclaved for 30 minutes at 15 lbs. steam pressure to make it sterile. A and B are aseptically combined, brought to correct volume with sterile water for injection, and mixed to homogeneity.

I claim:

1. A method of causing a tranquilizer eifect in warmblooded animals in need of a tranquilizer 'by administering to said animals an effective amount of a compound selected from the group consisting of (A) a free base having the formula gig in which R is methyl or ethyl, and

(B) an addition salt of (A) with a pharmaceutically acceptible acid.

2. A method of claim 1 wherein the active ingredient is administered parenterally at a dose of about 0.1 to 10 mg. per kilogram of body weight of the animal.

3. A method of claim 1 wherein the active ingredient is administered orally at a dose of about 0.3 to 30 mg. per kilogram of body weight of the animal.

4. A method of claim 3 wherein the tranquilizer eflFect is an anxiolytic effect.

5. A method of claim 4 wherein the active ingredient is administered at a dose of about 0.3 to 10 mg. per kilogram of body Weight of the animal.

6. A method of claim 3wherein the tranquilizer efiect is an antipsychotic effect.

7. A method of claim 6 wherein the active ingredient is administered at a dose of about 1 to 30 mg. per kilogram of body weight of the animal.

References Cited UNITED STATES PATENTS 3,457,271 7/1969 Cohen etal. 260296 STANLEY I. FRIEDMAN, Primary Examiner 

